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LETTER TO THE EDITOR Tissue-based chimerism analysis enhances detection of donor-derived neoplasia in allogeneic stem cell transplant patients Bone Marrow Transplantation (2017) 52, 634C637;

doi:10.

1038/ bmt.2016.332;

published online

19 December

2016 A number of cases of allogeneic hematopoietic stem cell transplant (allo-HCT) patients presenting with donor-derived neoplasms (DDN) has been reported.1,2 Even if the morphological ?ndings were identical, host-derived therapy-related myeloid neoplasms (t-MN) and DDN are distinct diseases, with potentially different treatments.3 However, the current World Health Organi- zation classi?cation does not distinguish them, which is mislead- ing, as the transplanted cells of DDN were never exposed to mutagenic agents used for the patient'

s original disease. On the basis of the distinct pathophysiology driving DDN versus therapy-related myeloid neoplasms, distinguishing them is clinically relevant. If a post allo-HCT neoplasm is determined to be host-derived, reduction of immunosuppression and donor lymphocyte infusion would be considered.4 This approach would not be favored if the new malignancy was donor-derived, in which case a search for another allogeneic stem cell donor could be warranted. No single diagnostic test cements the diagnosis of DDN. Molecular chimerism studies or conventional karyotyping (in gender-mismatched transplants) can establish genome-of-origin, provided that the sample is representative of the neoplastic population. However, it can be dif?cult to obtain a bone marrow aspirate suitable for chimerism studies in patients with marrow ?brosis. Here we report six new cases of DDN. Two of these highlight a weakness in the current diagnostic menu, as adequate aspirates were unavailable for chimerism studies. To circumvent this challenge, we conducted STR analysis directly from the core biopsy (please see Supplementary Data for methods of tissue dissection, DNA extraction and STR analysis). To our knowledge, these represent the ?rst two cases where chimerism analysis conducted on histologic tissue enabled the diagnosis of DDN. Case

1 A 57-year-old man with Sezary syndrome refractory to CHOP and vorinostat underwent matched sibling allo-HCT. A recurrence

2 years later was treated with radiation therapy, brentuximab and donor lymphocyte infusion. The skin lesions resolved, but pancytopenia developed, and he was diagnosed with AML

5 years post transplant. The marrow was inaspirable at the time of AML diagnosis;

biopsy showed 30% blasts with marked ?brosis (Figure 1). Chimerism studies, essentially performed on peripheral blood, showed 98% donor DNA, 2% recipient DNA. Peripheral blood showed only 6% leukemic blasts. Cytogenetics showed normal karyotype. Chimerism analysis performed directly on core biopsy contain- ing malignant blasts showed 90% donor DNA, con?rming DDN. The patient'

s brother,

54 at the time of donation, has remained healthy with normal complete blood count (CBC). The patient subsequently underwent an unrelated donor HCT. Case

2 A 69-year-old man with history of CLL with transformation to DLBCL was treated with R-CHOP followed by haploidentical transplant from his son. He also received post-transplant cyclophosphamide. Eighteen months post transplant, he devel- oped pancytopenia. His marrow showed AML with 60% blasts, dysplastic megakaryocytes and extensive ?brosis. The marrow was inaspirable and peripheral blood showed no leukemic blasts. Chimerism studies from peripheral blood showed 99% donor DNA, 1% recipient DNA. Cytogenetics showed abnormal male karyotype with loss or deletion of chromosomes